Xi-Ling Jiang (1, 2), Ping Zhao (2), Lawrence J. Lesko (1), Stephan Schmidt (1)
(1) Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, FL (2) Immediate Office, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA, Silver Spring, MD
Objectives:Â Acetaminophen (APAP) is available in more than 200 OTC and Rx products [1]. APAP poisoning is common in children because of accidental ingestion or overdosing [2]. Prediction of APAP pharmacokinetics (PK) in children is challenging, because the expression of enzymes involved in APAP elimination and bioactivation undergoes developmental changes [3,4]. The aim of this project was to develop a physiologically-based PK (PBPK) model for APAP that uses available information on the underlying enzymatic system and its maturation towards a mechanistic understanding of APAP metabolism and PP in children.
Methods:Â An APAP PBPK model was developed using Simcyp V12 with special emphasis on characterizing the contribution of all phase I (CYP1A2, 2E1, 3A4, etc.) and phase II (UGT1A1, 1A9, 2B15 and sulfotransferases) enzymes to APAP metabolism. This bottom-up approach was merged with a top-down approach to determine respective model parameters from published adult PK and pharmacogenetic data. The model was then qualified by predicitng adult PK data from independent studies using different dosing regimens in healthy subjects and cirrhosis patients. The model was subsequently used to predict APAP PK and metabolism in children across the entire age spectrum (neonates: 0-28 days to adolescents: 12-16 years) by accounting for age-dependent physiological differences.
Results:Â The PBPK model that was developed and qualified based on adult data was able to characterize i.v. and oral dosed APAP plasma PK profiles as well as changes in the urinary recovered APAP-glucuronide to APAP-sulfate ratio, which reflects the impact of enzyme ontogeny on APAP metabolism. The model-predicted changes in APAP clearance in children of different age groups were comparable to those estimated from an independent population PK analysis in children aged 37 weeks to 14 years [5].
Conclusions:Â A PBPK model containing detailed information on each enzyme known to substantially contribute to APAP metabolism successfully predicted APAP PK and metabolism in children after single and multiple dosing. This strategy of merging top-down and bottom-up approaches demonstrated the clinical utility of PBPK models for predicting PK in understudied populations, such as children, using in vitro data and PK data from adults. The model also may be used to identify subgroups and age ranges of children who are most susceptible to APAP-induced liver injury.
References:
[1]Â Ji, P., et al., Regulatory review of acetaminophen clinical pharmacology in young pediatric patients. J Pharm Sci, 2012. 101(12): p. 4383-9.
[2] Zhao, L. and Pickering G., Paracetamol metabolism and related genetic differences. Drug Metab Rev, 2011, 43(1): p. 41-52.
[3] Barrett, J.S., et al., Physiologically based pharmacokinetic (PBPK) modeling in children. Clin Pharmacol Ther, 2012. 92(1): p. 40-9.
[4] Johnson, T.N. and Rostami-Hodjegan, Resurgence in the use of physiologically based pharmacokinetic models in pediatric clinical pharmacology: parallel shift in incorporating the knowledge of biological elements and increased applicability to drug development and clinical practice. Paediatr Anaesth, 2011. 21(3): p. 291-301.
[5] Strougo, A. et al., First dose in children: physiological insights into pharmacokinetic scaling approaches and their implications in paediatric drug development. J Pharmacokinet Pharmacodyn, 2012. 39(2): 195-203.
Reference: PAGE 22 (2013) Abstr 2945 [www.page-meeting.org/?abstract=2945]
Poster: Absorption and Physiology-Based PK